The Rate of Bone Loss Slows After 1–2 Years of Initial Antiretroviral Therapy

Final Results of the Strategic Timing of Antiretroviral Therapy (START) Bone Mineral Density Substudy

A Carr; B Grund; AV Schwartz; A Avihingsanon; S Badal-Faesen; JI Bernadino; V Estrada; A La Rosa; PWG Mallon; S Pujari; D White; N Wyman Engen; K Ensrud; JF Hoy


HIV Medicine. 2020;21(1):64-70. 

In This Article

Abstract and Introduction


Objectives: Initial antiretroviral therapy (ART) causes loss of bone mineral density (BMD) over the first 1–2 years. Whether this loss continues with longer therapy is unclear. We determined changes in bone and spine BMD over 5 years in adults receiving immediate or deferred initial ART.

Methods: In the Strategic Timing of Antiretroviral Therapy (START) BMD substudy, ART-naïve adults with CD4 counts > 500 cells/μL were randomized to immediate or deferred ART. Deferred group participants not yet on ART were offered ART after May 2015. Mean per cent changes in total hip and lumbar spine BMD (measured annually by dual-energy X-ray absorptiometry) were compared between groups using longitudinal mixed models. Fracture rates were also compared between groups for all START participants.

Results: Substudy participants (immediate group, n = 201; deferred group, n = 210; median age 32 years; 80% non-white; 24% female) were followed for a mean 4.5 years until December 2016. In the immediate group, > 96% used ART throughout. In the deferred group, 16%, 58% and 94% used ART at years 1, 3 and 5, respectively. BMD decreased more in the immediate group initially; groups had converged by year 3 at the spine and year 4 at the hip by intent-to-treat (ITT). BMD changes after year 1 were similar in the immediate group and in those off ART in the deferred group [mean difference: spine, 0.03% per year; 95% confidence interval (CI) −0.4, 0.4; P = 0.88; hip, −0.2% per year; 95% CI −0.7, 0.3; P = 0.37]. Fracture incidence did not differ significantly between groups (immediate group, 0.86/100 person-years versus deferred group, 0.85/100 person-years; hazard ratio 1.01; 95% CI 0.76, 1.35; P = 0.98).

Conclusions: Significant ART-induced bone loss slowed after the first year of ART and became similar to that in untreated HIV infection.


Bone mineral density (BMD) declines in the first 1 to 2 years of initial antiretroviral therapy (ART).[1] This decline is greater in those receiving tenofovir disoproxil fumarate (TDF) and/or a boosted protease inhibitor. But even in those not receiving either of these medications, there appears to be a decline of about 1% over 1–2 years,[2–5] a decline that is greater than would be expected in a young adult population and has been attributed to altered immune function following suppression of HIV replication.[6,7]

Whether BMD continues to decline after the first year of initial ART is less clear. Some studies have reported stable BMD after year 1,[8] in some cases up to year 5.[9] But other studies have reported ongoing decline.[10] Unfortunately, most studies only have follow-up of 1 or 2 years.

Data on the impact of treated versus untreated HIV infection are sparse. The International Network for Strategic Initiatives in Global HIV Trials Strategic Timing of Antiretroviral Therapy (START) study randomized ART-naïve adults with CD4 lymphocyte counts > 500 cells/μL to immediate ART versus deferring ART until CD4 count < 350 cells/μL; participants in the deferred group were advised to commence ART, after a planned analysis in May 2015 found that immediate ART decreased the risk of clinical events. At that time, we reported that immediate ART in the START BMD substudy resulted in steeper BMD decline (1–2%) relative to deferred ART after a mean follow-up of 2.2 years.[11] After May 2015, all participants were offered ART. We now report final START BMD data collected up to December 2016 after a mean follow-up of 4.5 years, complemented with fracture data collected for all participants in the parent START study.